This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The objectives of this project were to: (1) Perform a cross-sectional analysis of HIV adaptation to HLA-class I restricted immune responses at population and individual levels to determine if HIV-1 polymorphisms associated with HLA alleles cluster within known HLA class I specific CD8+ CTL epitopes and if we can identify novel epitopes that are specific to African HLA alleles, (2) Determine the kinetics of CTL epitope escape and reversion in 150 couples involving recent transmission as the virus adapts in moving from one HLA class I environment in the donor to that of the recipient, (3) Determine in 40 high-risk non-transmitting couples if long-term non-transmitting partners display a bias in escape signatures that contribute to the lack of transmission. These studies elucidated mechanisms by which HIV escapes the host's immune response, benefiting future vaccine design. Gag and nef sequences from 200 chronically infected non-transmitters and 150 chronically infected transmitters have been completed and are used for a comprehensive HLA-linked polymorphism analysis. Class I HLA typing and viral load analyses were also completed for these subjects. In newly infected subjects, gag-specific escape mutations inherited from the donor were inversely correlated with early viral loads, suggesting these mutations adversely affected viral fitness. Three p24 Gag escape mutations in HLA-B*5703 positive subjects occurred in a predictable order and mutations were accompanied by increased viral loads suggesting a loss of immune control. KIR genotyping was completed for 205 seroconverters and 224 exposed uninfected partners to examine how KIR and HLA gene expression might affect viral protection. Class II DRB1 and DQB1 genotyping were completed in nearly 200 couples. Finally, results from a 9-cohort study showed the frequency of certain epitope variants was highly correlated with the abundance of the restricting HLA allele, suggesting viral adaptation to HLA pressure within the population.